Abstract

The essential role of ubiquitin in a variety of processes involving protein turnover is now well- established, but central mechanistic features of the multienzyme ubiquitin pathway remain unelucidated. This proposal describes a broad- ranging research program in which engineered ubiquitin fusions will be used to study a number of important features of the ubiquitin pathway, and molecular genetic methods will be used to characterize a number of newly-discovered pathway components. Areas to be addressed include: developing a method to evaluate whether co- translational protein turnover occurs; studies on the mechanics of protein degradation by the proteasome; analysis of the degradation of hybrid proteins containing nearly-identical domains which, when separated, are degraded at divergent rates; a functional and mechanistic analysis of a novel relative of ubiquitin activating enzyme; and a biochemical and genetic analysis of a family of components that are part of a novel `arm' of the ubiquitin pathway. These studies will be carried out mainly in the yeast S. cerevisiae, in which analysis of the ubiquitin pathway is already far advanced.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM031530-17
Application #
2684747
Study Section
Biochemistry Study Section (BIO)
Project Start
1992-07-01
Project End
1999-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
17
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
California Institute of Technology
Department
Type
Schools of Arts and Sciences
DUNS #
078731668
City
Pasadena
State
CA
Country
United States
Zip Code
91125

  Publications

Kim, Jeong-Mok; Seok, Ok-Hee; Ju, Shinyeong et al. (2018) Formyl-methionine as an N-degron of a eukaryotic N-end rule pathway. Science 362:
Chen, Shun-Jia; Wu, Xia; Wadas, Brandon et al. (2017) An N-end rule pathway that recognizes proline and destroys gluconeogenic enzymes. Science 355:
Oh, Jang-Hyun; Chen, Shun-Jia; Varshavsky, Alexander (2017) A reference-based protein degradation assay without global translation inhibitors. J Biol Chem 292:21457-21465
Oh, Jang-Hyun; Hyun, Ju-Yeon; Varshavsky, Alexander (2017) Control of Hsp90 chaperone and its clients by N-terminal acetylation and the N-end rule pathway. Proc Natl Acad Sci U S A 114:E4370-E4379
Wadas, Brandon; Piatkov, Konstantin I; Brower, Christopher S et al. (2016) Analyzing N-terminal Arginylation through the Use of Peptide Arrays and Degradation Assays. J Biol Chem 291:20976-20992
Liu, Yu-Jiao; Liu, Chao; Chang, ZeNan et al. (2016) Degradation of the Separase-cleaved Rec8, a Meiotic Cohesin Subunit, by the N-end Rule Pathway. J Biol Chem 291:7426-38
Wadas, Brandon; Borjigin, Jimo; Huang, Zheping et al. (2016) Degradation of Serotonin N-Acetyltransferase, a Circadian Regulator, by the N-end Rule Pathway. J Biol Chem 291:17178-96
Piatkov, Konstantin I; Vu, Tri T M; Hwang, Cheol-Sang et al. (2015) Formyl-methionine as a degradation signal at the N-termini of bacterial proteins. Microb Cell 2:376-393
Park, Sang-Eun; Kim, Jeong-Mok; Seok, Ok-Hee et al. (2015) Control of mammalian G protein signaling by N-terminal acetylation and the N-end rule pathway. Science 347:1249-1252
Varshavsky, Alexander (2014) Discovery of the biology of the ubiquitin system. JAMA 311:1969-70

Showing the most recent 10 out of 89 publications